Structure−Activity Relationships of the Cycloalkanol Ethylamine Scaffold: Discovery of Selective Norepinephrine Reuptake Inhibitors

详细信息    查看全文

• 作者：Paige E. Mahaney ; Lori K. Gavrin ; Eugene J. Trybulski ; Gary P. Stack ; An T. Vu ; Stephen T. Cohn ; Fei Ye ; Justin K. Belardi ; Arthur A. Santilli ; Joseph P. Sabatucci ; Jennifer Leiter ; Grace H. Johnston
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：July 10, 2008
• 年：2008
• 卷：51
• 期：13
• 页码：4038 - 4049
• 全文大小：198K
• 年卷期：v.51,no.13(July 10, 2008)
• ISSN：1520-4804

文摘

Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine (1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified (S)-(−)-17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC₅₀ = 82 nM, K_i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.